Apoptosis in NK Cells. Activation-induced death in NK cells occurs when NK cells are activated with IL-2 or IL- 12 prior to receptor cross-linking or aggregated Ig induced apoptosis. Many of the other cytokines tested are able to activate NK cytotoxicity [IL-6, IL-7, IFN-alpha & IFN-gamma], or induced gene transcription [IL-6, IL-7, IL-13, IFN-alpha & IFN-gamma]. The exact nature of the activation signal required for receptor-induced killing is unknown; however, both IL-2 and IL-12 induce NK cell proliferation, a demonstrated requirement for TcR-induced apoptosis. Our recent studies examined the involvement of TNF receptor family members or Fas in this rapid cell death. These studies demonstrated a requirement for cell contact, however, unlike cell-mediated lysis, extracellular calcium was not required. Antibodies directed against Fas, TNFR60, TNFR80, LTBR, and LTa failed to inhibit receptor-induced death. Therefore, NK cells appear to demonstrate a rapid apoptotic episode when CD16 is cross linked, but the mechanism of this apoptosis appears distinct from surface moieties used in T cells. The direct examination of the Fas pathway on activated NK cells revealed that a protracted kinetic susceptibility. Therefore, NK cells can demonstrate an apoptotic response to both CD16 and Fas, but with a considerably different kinetic and quantitative response. Chemokine Regulation of NK Cells. 1. NK cell chemotaxis studies revealed that macrophage inflammatory protein-1alpha (MIP-1alpha) and interferon-inducible protein-10 (IP-10) are potent NK cell chemoattractants in vitro. Modest migratory responses also were observed in response to IL-2 and chemokines RANTES, MCP-1, MCP-2, MCP-3, and MIP-1beta. Chemokine receptor expression on human NK cells revealed the presence of both distinct and shared chemokine receptors. These results demonstrate that NK cells express functional chemokine receptors that mediate NK cell chemotaxis and may represent an important means in the recruitment of NK cells to inflammatory sites in vivo. 2. Chemokines have been shown to induce the directional migration. We have demonstrated that chemokines MIP-1alpha, RANTES, MCP-1, and IP-10 are capable of augmenting NK-specific cytolytic responses in both a dose- and donor-dependent fashion. Together, these results suggest that chemokines not only play an important role in the recruitment of NK cells to sites of inflammation, but may be important autocrine and paracrine mediators of NK cell degranulation augmenting local tumor cell destruction.